Cardiac atrial natriuretic peptide (ANP) exerts important endocrine effects regulating arterial blood pressure and intravascular volume. Our observations in genetic mouse models indicate that, in addition to endocrine actions, ANP has important autocrine and paracrine functions functions within the heart. These include regulation of myocyte growth, inhibition of fibroblast proliferation and extracellular matrix deposition, and proangiogenic effects. All these actions are mediated by the guanylyl cyclase-A (GC-A) receptor and elevation of the second messenger cyclic GMP. In cardiomyocytes, cGMP-dependent protein kinase I (PKG I) stimulates regulator of G protein signaling 2, inhibiting Gq-coupled stimuli. This signaling pathway mediates the counterregulation of the Ca²⁺_i and growth -stimulating effects of Angiotensin II by local ANP. ANP plasma levels are markedly increased in chronic hypertensive heart disease. Yet GC-A - mediated cGMP formation is significantly blunted due to dephosphorylation and homologous desensitization of the receptor. Here we have discovered a novel cGMP-independent signaling pathway of GC-A, which involves a stable complex of GC-A and transient receptor potential canonical (TRPC3/C6) channels. This complex changes its conformation upon ANP binding, modulating the activity of the channels and ultimately increasing myocyte Ca²⁺_i-levels. Our results demonstrate for the first time that the ANP/GC-A system exerts dual effects on cardiac myocytes. Under physiological conditions cGMP formation moderates the action of hypertrophic factors. However, under pathophysiological conditions, when GC-A is desensitized by high ANP levels, a cGMP-independent signaling function of the receptor might increase the propensity to hypertrophy and arrhythmias. Supported by SFB 487 and SFB 688